Transcript of "Current Management of Anovulatory Infertility"

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N Anovulation is the failure to release an oocyte from a mature graafianfollicle during a menstrual cycle (in a post-menarcheal, premenopausalwoman) Usually manifests itself as irregularity of menstrual periods, that is,unpredictable variability of intervals, duration, or bleeding Most of these women have oligomenorrhea, arbitrarily defined asmenstruation that occurs at intervals of 35 days to six months. Infertility is the inability of a couple to achieve pregnancy after twelvemonths of adequate unprotected sexual intercourse. 14% of couples according to this criteria (9% primary, 5% secondary) Anovulatory infertility affects a large proportion of reproductive-agedwomen Commonest cause of infertility in developed countries

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N Up to 40%, representing 5 million couples in the United States alone(Barbieri 1999; Hull 1987) Studies from Nigeria 20% of cases, more common causes of infertilitybeing tubal factors 34.4% [Giwa-osagie OF et al Int J. of fertility 198429(2)] Increasing concern in terms of maintaining a sufficiently large andrelatively youthful workforce Heightened stress on the woman and couple, with significant financialstrain on the family and society The costs per pregnancy of three different strategies were compared,with a threshold for cost-effectiveness of €10 000 [Marinus J.C. et al Ox. Jof humRep 2005 20(10)] A structured approach, starting with low-cost interventions andadvancing to high resource interventions, is warranted for treatment ofanovulatory infertility

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R Laparoscopic ovarian drilling (LOD) is associated with an increased risk ofmultiple Pregnancy Premature ovarian failure is irreversible More triplets, quadruplets and quintuplets are born as a result of in vitrofertilisation/intracytoplasmic sperm injection (IVF/ICSI) than ovulationinduction 50% of all women achieving pregnancy do so on the 50 mg dose ofclomid OHSS does not occur in the absence of luteinisation by human chorionicgonadotrophin or luteinizing hormone (LH). OHSS is seen more often in women who are obese. Evidence suggests that recombinant FSH results in better pregnancy ratesthan purified FSH.

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MANAGEMENT Most of these approaches are effective for WHO class 2 patients. WHO class 1 patients respond best to therapy involving lifestylemodification or gonadotropins. Some WHO class 3 patients respond to gonadotropin therapy and in vitrofertilization (IVF), but those who fail require oocyte donation Adequate history and physical examination are essential. Adequate patient counseling/patient information leaflets Correct any underlying disorder Optimize health before starting therapy Exclude other causes of infertility (semen analysis, tests of tubal patency,TFT etc. as indicated) Induce regular unifollicular ovulation

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NS Ultrasonography :- Size; as ovaries depleted of eggs tend to be smaller- Follicular tracking, Ovulation is deemed to have occurred if the folliclereached a mean diameter of 18–25 mm and subsequently changed insize, shape, or sonographic density. The changes in ultrasound image of the follicle that rupture are:(1) disappearance or sudden decrease in size(2) increased echogenicity(3) irregularity of follicular wall(4) appearance of free fluid in the cul de sac of Douglas. Disappearance or sudden decrease in follicle size has been found to bethe most frequent sign of ovulation. Sensitivity and specificity ofultrasonography to document ovulation is 84% and 89%, respectively,and accuracy is about 85%

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NS Anti-Mullerian Hormone (AMH) testing:- correlates with the number of antral follicles in the ovaries- levels do not vary with the menstrual cycle and can be measuredindependently of the day of the menstrual cycle and decrease with age.- Healthy women, below 38 years old, with normal follicular status at day3 of the menstrual cycle, have AMH levels of 2.0 - 6.8 ng/ml (14.28 -48.55 pmol/L).- High levels are found in patients with PCOD, which compromises femalefertility Antral follicle count/Ovarian reserve:- Counted by vaginal USS- along with female age, the best tool that we currently have forestimating ovarian reserve, the expected response to ovarian stimulatingdrugs, and the chance for successful pregnancy with in vitro fertilization.

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TREATMENT OPTIONS FOR WHO GROUP I (HYPOGONADOTROPICHYPOGONADISM) Supervised programs for weight optimization. Pulsatile administration of gonadotrophin-releasing hormone (GnRH)agonists. Gonadotrophin (with LH activity) regimens. GnRH, administered subcutaneously (15–20 micrograms usually every 90minutes) or intravenously (5 micrograms every 90minutes) in a pulsatilemanner through a pump Gonadotrophins regimens are discussed later under treatment optionsfor who group II For WHO group I ovulatory disorders, gonadotrophins with luteinizingactivity are better at inducing ovulation than pure FSH preparations. Clomiphene is ineffective in the absence of an intact hypothalamic–pituitary axis and therefore it is not appropriate as a treatment in thisgroup of anovulatory women

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TREATMENT OPTIONS FOR WHO GROUP II NORMOGONADOTROPHICANOVULATION Heterogeneous group of patients who can present either with regularcycles, oligomenorrhoea, or even amenorrhoea. Most of these patients are likely to have PCOS (~80%) Other causes include congenital adrenal hyperplasia, adrenal tumours,and androgen-producing ovarian tumors The patient may have clinical symptoms or signs of hyperandrogenismsuch as hirsutism, which should require more detailed investigations suchas measurement of dehydro-epianderosterone sulphate and 17-OHprogesterone Specific causes, such as adrenal or ovarian tumours, should be treated byremoving the cause. Congenital adrenal hyperplasia benefits fromcorticosteroid therapy.

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SYNDROME (PCOS) PCOS is a heterogeneous collection of signs and symptoms that, gatheredtogether, form a spectrum of a disorder with a mild presentation insome, whilst in others it causes severe disturbance of reproductive,endocrine and metabolic function:- Oligo- and/or anovulation- Hyperandrogenism (clinical and/or biochemical);- Polycystic ovaries, with the exclusion of other etiologies. Treatment: Effective use of ovulation induction agents. requires understanding of their mechanism of action, proper indications,different regimens, monitoring methods, and potential complications.

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SYNDROME (PCOS)Points To Consider Before Ovulation Induction:i. Selection of appropriate treatmentii. Total motile sperm count of at least five million/ejaculate.iii. Advice on weight control (gain/loss to achieve a BMI of <30kg/m2 or>20kg/m2)iv. Adequate counselling of women regarding the risks of treatmentv. Ovulation induction should only be started if adequate monitoringfacilities (ultrasound and laboratory) are available, together withprotocols with clear guidelines for reducing risks, which would includecancellation of treatment cycles.

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SYNDROME (PCOS)MEDICAL INDUCTION OF OVULATION ANTI-ESTROGENS:1. Clomiphene Citrate (CC) First Line, Safe Effective, Cheap, Orally Administered Mechanism Of Action- Displaces Endogenous Oestrogen from OestrogenReceptors In The Hypothalamic-pituitary Axis, Which Diminishes ItsNegative Feedback And Increases The Secretion Of GnRH and thusGonadotrophins. Regimen and monitoring - 50 mg per day for five days following Aspontaneous or progestin-induced withdrawal bleeding. Starting from day 2, 3, 4 or 5 of the cycle was not shown to influence theresults Duration of treatment- generally limited to six (ovulatory cycles) withmaximum of 12 in total

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SYNDROME (PCOS)CC IN COMBINATION With Tamoxifen (20mg) : no significant difference in ovulation andpregnancy rates With Ketoconazole (400mg) : no difference in single pregnancy, multiplepregnancy, miscarriage rates With Bromocriptine (7.5mg) : no difference in pregnancy and ovulationrates With Dexamethasone (2mg) : 3-fold increase benefit in pregnancy rate With COCP : increased ovulatory and pregnancy rates but no differencein miscarriage rate With B-HCG : no difference in pregnancy and spontaneous abortion rates

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SYNDROME (PCOS)2. Tamoxifen A Triphenylethylene derivative with a structure similar to CC. The suggested dose in ovulation induction is 20-40 mg daily, beginning oncycle day 3 for 5 days Efficacy and safety of Tamoxifen is similar to CC ovulation rates, with nosignificant difference in pregnancy rates per cycle, and no difference inincidence of miscarriage rates. While ovulation induction has been shown, Tamoxifen is not licensed forthat purpose and patients should be counseled for its off-label use

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SYNDROME (PCOS) INSULIN SENSITIZING AGENTS:1. Metformin In theory, improves insulin resistance and consequently ovulatory status. Regimen- 500 mg tds or 850 mg bd with meals, titrated. May provide an alternative for obese patients with clomipheneresistance. Metformin can be offered to obese and non-obese anovulatory womenwith PCOS Nevertheless, the use of metformin as a preferred ovulation inductionagent in obese women remains a matter of controversy Another potential advantage of metformin is that it may have a weightreducing effect, although this also remains a matter of controversy. Avoids the increased risk of multiple pregnancies (4-11%), and ovariancancer (prolonged use more than 12 months) associated withclomiphene

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SYNDROME (PCOS)EFFICACY(a) Metformin monotherapy Metformin used alone improves the ovulation rate and clinical pregnancyrate compared with placebo or no treatment, but not the live birth rate. Compared with CC, metformin gives lower ovulation rate and clinicalpregnancy rate and a non-significant trend of lower live birth rate. There are no difference in the miscarriage rate and the multiplepregnancy rate between the two treatments(b) Metformin co-treatment with CC Co-treatment with metformin and CC compared with CC only improvesthe ovulation rate and clinical pregnancy rate in obese patients but not innon-obese patients Improves live birth rates inclusive in CC resistant women only

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SYNDROME (PCOS)SIDE EFFECTS dose-dependent G.I symptoms Lactic acidosis is a rare though serious complication, and hencemetformin should not be prescribed to patients with renal, hepatic ormajor cardiovascular disease or hypoxia.2. Use of other insulin sensitizing agents: rosiglitazone and pioglitazone. rosiglitazone improved ovulation rate but result in a higher incidence ofweight gain On the other hand, these drugs are classified as FDA category C. There is no data on the role of pioglitazone in fertility treatment

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SYNDROME (PCOS)AROMATASE INHIBITORS:Letrozole, 3rd generation AI gaining in popularity as an agent for ovulation induction in patients withPCOS. Its use in combination with gonadotrophin in ovarian stimulationprotocol for patients, in whom high oestradiol level would becontraindicated, for example breast cancer patients, is also advocated does not have the anti-oestrogenic effects and has a much shorter halflife (~45hrs) [CC: 5-7days] Use in ovulation induction is an off-label use.

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SYNDROME (PCOS)REGIMEN AND MONITORING The regimen is 2.5 to 5 mg per day for five days from day 3-7 of theperiod, or as a single dose of 20 mg on day 3 of the period. A prolonged duration for 10 days has being evaluated.SIDE EFFECTS Letrozole is well tolerated. Fatigue, nausea, constipation, diarrhea, headache, drowsiness anddizziness are common side effects. Multiple pregnancy rate was significantly lower in Letrozole, both 2.5 mgdaily or 5 mg daily, comparing with CC treatment as the letrozoletreatment gave more monofollicular development comparing with CC

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SYNDROME (PCOS)GONADOTROPHINSMECHANISM OF ACTIONThe use of exogenous gonadotrophins is to overcome the FSH thresholdrequired for the follicular development

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SYNDROME (PCOS)REGIMENS First line therapy for anovulatory patients who have failed to ovulate orconceive after clomiphene citrate treatment Extremely effective in both World Health Organization (WHO) groupII/polycystic ovary syndrome (PCOS) patients and in WHO groupI/hypogonadotrophic hypogonadal patients (WHO, 1973; Balen et al.,1994) Drug dose should be individualized to get the best result. ‘Soft’ protocols developed to minimize the risk of multiple ovulation

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SYNDROME (PCOS) “Conventional dose step-up” regime:. 75-150 iu/day started on day 2-3 of the cycle, is increased by 75iu/day every 3-5 days till ovarian response is evident.. compared to the “chronic low-dose step up” approach:. duration of stimulation is shorter but the incidence of multiplepregnancy and OHSS is higher, especially in patients with PCOS. Chronic low-dose, step-up protocol:. currently the recommended protocol in many centers worldwide. low starting dose (37.5-75 IU/day) for at least 10-14 days and thedaily dose is increased by 37.5 IU at weekly intervals up to a maximum of225 IU/day.. Once 1 to 2 dominant follicles reach 18 mm in mean diameter, hCG isgiven at a dose of 5000-10000 IU to induce ovulation.

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SYNDROME (PCOS) Step-down protocol:. Aim is to mimic the physiological changes of normal cycles.. FSH injection started at 150 IU/day starting day 2-3 of the cycle andovarian response is monitored by transvaginal scanning every 2-3 days.. dose is continued until a dominant follicle ≥10mm is seen on scanning,then ↓ to 112.5 IU/day followed by a further decrease to 75 iu/d 3 dayslater. continued until hCG is administered to induce ovulation. Hence itrequires more intense monitoring than the step up protocol. shorter duration of stimulation compared to the step up protocol, but ahigher rate of multifollicular development and OHSS as well as a lowerovulation rate.. pregnancy rate is comparable between the two regimes.

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SYNDROME (PCOS)CONCOMITANT USE:1. With GnRH agonists (Goserelin) Starting on day 21 of cycle prior to gonadotrophin administration willlower the tonic high LH concentrations during the follicular phase prevents the occurrence of premature LH surges. This may be used inpatients with a previous history of premature luteinisation. ↑se cost2. With CC lessen the overall cost by ↓ the amount of gonadotrophin needed. CC 100mg daily from days 2–6 for follicular recruitment, thengonadotrophin 150IU daily or on alternate days to promote folliculargrowth

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SYNDROME (PCOS) ↓se the gonadotrophin requirement by up to 50%, hence cost. used in anovulatory patients who have endogenous gonadotrophins.MONITORING OF OVARIAN RESPONSE to allow for adjustment of the gonadotrophin dose timing the hCG injection for ovulation trigger and cancellation of cycles with excessive response. both serum oestradiol concentrations and ultrasound examination arecommonly used for monitoring purposes.

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SYNDROME (PCOS)HIGH RESPONDERSenlarged ovaries, large no of follicles, elevated serum estradiol(>3000pg/ml)(A) Coasting. To continue GnRH agonist. No gonadotrophin stimulation. To give hCG once oestradiol level is within the normal range(B) To cancel the treatment cycle, higher rate in women with BMI >25kg/m²(C) Follicular puncture, oocyte retrieval with IVF(D) Ovarian electrocautery with follicular aspiration(E) Embryo cryopreservation (used in next cycle)(F) Avoiding use of hCG for luteal support (progesterone used)(G) Use of recombinant LH preparations with short half life.

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SYNDROME (PCOS)POOR RESPONDERSfewer follicles (<3) serum oestradiol <500pg/ml. To use higher dose of gonadotrophin stimulation. To decrease the doses of GnRH agonists. To use GnRH antagonists, early onset of action and longer half life, in latefollicular phase, prevent LH surge and does not interrupt folliculogenesisSIDE-EFFECTSSerious complications of gonadotrophin therapy include: ovarian hyperstimulation syndrome multiple pregnancy. Other complications include local reaction at the site of the injection rarely anaphylactic reaction, perhaps due to the protein content of theurinary products. Switch to recombinant FSH preparations

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SYNDROME (PCOS)GONADOTROPHIN-RELEASING HORMONE (GnRH)MECHANISM OF ACTION GnRH administered in a pulsatile fashion restores the normal pattern of gonadotrophin secretion of a spontaneousmenstrual cycle, leading to the development of a single dominant follicle. Hypogonadotropic patients of normal or low weight are the bestcandidates for this treatment. A cumulative pregnancy rate of 80% after six cycles and up to 93% after12 has been reported. It is recommended to continue this therapy for at least 12 cycles in theabsence of other subfertility factors

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SYNDROME (PCOS)REGIMEN AND MONITORING SC/IV route through a small butterfly cannula using a small battery-operated pump which delivers 2.5–20.0mcg per bolus at 60-120 minuteintervals. The IV route is preferred by some because more physiological LH profilesand higher ovulatory rates result when GnRH is administeredintravenously. Higher dosage (10 mcg per bolus) given at lower intervals (120 minutes)are just as effective as lower dosage (2-5mcg per bolus) given at a higherrate (every 60-90 minutes) Treatment can be monitored by regular serum oestradiol measurementsand pelvic ultrasound at regular intervals. Couples are advised to have regular intercourse during the treatmentcycle.

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SYNDROME (PCOS) The luteal phase has to be supported, either by continuing with the sameregimen of pulsatile GnRH administration or using exogenous hcginjections. Zoladex 3.6mg SC every 28days, and a vial costing about N30000SIDE-EFFECTS Multiple pregnancy . This risk can be greatly reduced if lower pulsedosages are employed at a lower frequency for the first cycle. OHSS has never been described with pulsatile GnRH administration. Patients may be reluctant to use the pulsatile GnRH therapy because ofinconvenience, worry about pump failure and the problems of the needlebeing left in situ for a long time (e.g. displacement, local reaction,infection)

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SYNDROME (PCOS)SURGICAL INDUCTION OF OVULATION second-line treatment modality for PCOS women who fail to respond toCC Wedge resection of ovary; discarded. Laparoscopy ovarian drilling; uses monopolar diathermy. minimal tissue handling. less risk of adhesions (10-20%). further reduced with use of periovarian coolant [ 1L Adept℗ solutioninstilled into pouch of douglas]. Rules of 4: number of diathermy points minimized to 4 per ovary for 4seconds at 40watts.. adhesions formed is fine and of little clinical significance

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TREATMENT OPTIONS FOR WHO GROUP IV(HYPERPROLACTINAEMIA) found in 15% of women with anovulation, and in 75% of women withboth anovulation and galactorrhoea High levels of prolactin interfere with the pulsatile release of GnRH fromthe hypothalamus. This, in turn, interferes with pituitary gonadotrophinsecretion, resulting in oestrogen-deficient amenorrhoea and subfertility. Sustained hyperprolactinaemia, with levels of greater than 1000 mU/l*needs evaluation, including pituitary imaging.Causes include: Microadenoma; rarely, macroadenoma of the pituitary Idiopathic (pituitary neoplasm too small, <5mm, to be seen on CT scan) Hypothyroidism, renal or hepatic dysfunction Dopaminergic antagonists, such as Phenothiazines Physiological factors, such as pregnancy, lactation and stress

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TREATMENT OPTIONS FOR WHO GROUP IV(HYPERPROLACTINAEMIA) Women with polycystic ovaries; not PCOS (about 9% of women withpolycystic ovaries have a raised prolactin level)INDICATIONS FOR TREATMENT hyperprolactinaemia results in a hypo-oestrogenic state, threateningskeletal integrity, treatment is advocated in all young women, even ifinfertility is not an issue. In older women, bone density scanning is a useful indicator to seewhether treatment would be beneficial.TREATMENT MODALITIES1. Medical therapy: mainline of treatment; first-line treatment is the use of dopamineagonists, lowers prolactin concentration and cause shrinkage of aprolactinoma if present. Bromocriptine 2.5 to 20 mg in divided doses 2-3 times a day

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TREATMENT OPTIONS FOR WHO GROUP IV(HYPERPROLACTINAEMIA) If pregnancy occurs while a woman is taking a dopamine agonist, thecurrent practice is to stop the drug. However, in women with large prolactinomas that may enlarge inpregnancy, this may be unnecessary; weighing the risk-benefit ratio.2. Surgery: trans-sphenoidal pituitary adenomectomy is seldom indicated in thepresence of a prolactinoma because of high recurrence rate andpossibility of panhypopituitism. may be indicated for women with large macroadenomas resistant to drugtreatment or where, despite normalisation of prolactin levels, no tumourshrinkage is seen.3. Radiotherapy is used very infrequently and is considered only if both medical andsurgical treatments fail or are contraindicated.

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STUDY HISTORY:Mrs. C. B is 32 years old, oligomenorrheic with confirmed polycystic ovariesby USS. Her last period was 6 weeks prior to presentation and she isuncertain as to when her next period will be. She presents to us fortreatment of primary infertility of 3 years duration. Her husband is 34 yearsold, fit and well, with no significant past history of note. He has had onechild aged 7 years from a previous relationship. Other causes of herinfertility were effectively ruled out in the detailed history. EXAMINATION:Mrs. C. B has a BMI of 31 and has no abnormalities detected on anabdominal or pelvic examination, and her husbands recent semen analysisis within normal limits.

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STUDY TREATMENT:1. Adequate Counselling on nature of her infertility2. Advise weight reduction3. Induced a withdrawal bleed with oral progesterone4. Gave clomiphene at a dose of 50mg daily for 5 days, starting onsecond day of her bleed5. Timed sexual intercourse FOLLOW UPAfter three cycles of clomifene at the 50mg dose, Mrs. C.B returnedwith a Positive Pregnancy Test, and she is presently booked in ourAntenatal clinic.

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TEASER Laparoscopic ovarian drilling (LOD) is associated with an increased risk ofmultiple Pregnancy Premature ovarian failure is irreversible More triplets, quadruplets and quintuplets are born as a result of in vitrofertilisation/intracytoplasmic sperm injection (IVF/ICSI) than ovulationinduction 50% of all women ON CLOMIPHENE achieving pregnancy do so on the 50mg dose OHSS does not occur in the absence of luteinisation by human chorionicgonadotrophin or luteinizing hormone (LH) OHSS is seen more often in women who are obese Evidence suggests that recombinant FSH results in better pregnancy ratesthan purified FSH

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NT The work was supported by my Supervisor, Dr. OluseyiAtanda. I thank him for his patience, encouragementand insightful corrections. My Senior registrars for their understanding andsupport. All my fellow registrars; worthy of mention, Dr. Bajowa,for the many corrections and additions and suggestionof materials to include. Dr. O.F Ojo for her proof-reading and ensuring Icomplete in a timely manner. There is no conflict of interest